The N-terminal tails of core histones are covalently modified by post-translational modifications, including acetylation and phosphorylation. Evidence suggests that these covalent modifications play important roles in several biological activities involving chromatin, e.g., transcription and replication. Histone deacetylases (HDACs) catalyze the removal of the acetyl group from the lysine residues in the N-terminal tails of nucleosomal core histones resulting in a more compact chromatin structure, a configuration that is generally associated with repression of transcription.
Five proteins and/or open reading frames in yeast (RPD3, HDA1, HOS1, HOS2 and HOS3) that share significant homology in the catalytic domain have been identified as HDACs based upon their sequence homology to human HDAC1. To date, eight HDACs have been identified in mammalian cells, and classified into two classes based on their structure and similarity to yeast RPD3 or HDA1 proteins. Recently, Sir2 family proteins that are structurally unrelated to the five proteins aforementioned have been identified as NAD-dependent HDACs. Class I HDACs are the yeast RPD3 homologs HDAC1, 2, 3, and 8, and are composed primarily of a catalytic domain. Class II HDACs are the yeast HDA1 homologs HDAC4, 5, 6, and 7. HDAC4, 5, and 7 contain a long non-catalytic N-terminal end and a C-terminal HDAC catalytic domain while HDAC6 has two HDAC catalytic domains.
It has also been determined that histone deacetylases can be sensitive to small molecules, including trichostatin A (TSA), trapoxin, and butyrate. For example, the yeast RPD3 and HDA1 and mammalian HDAC1, 2, 3, 4, 5, 6, 7 and 8 are sensitive to inhibition by trichostatin A (TSA). The Sir2 family HDACs, yeast HOS3 and Drosophila melanogaster dHDAC6, however, appear to be relatively insensitive to TSA. A class of hybrid bipolar compounds, such as suberoylanilide hydroxamic acid (SAHA) have also been shown to inhibit histone deacetylases and induce terminal differentiation and/or apoptosis in various transformed cells. Examples of such compounds can be found in U.S. Pat. No. 5,369,108, issued on Nov. 29, 1994, U.S. Pat. No. 5,700,811, issued on Dec. 23, 1997, and U.S. Pat. No. 5,773,474, issued on Jun. 30, 1998 to Breslow et al., as well as U.S. Pat. No. 5,055,608, issued on Oct. 8, 1991, and U.S. Pat. No. 5,175,191, issued on Dec. 29, 1992 to Marks et al., the entire content of all of which are hereby incorporated by reference.
The identification of the mechanisms by which histones are deacetylated, and the characterization of histone deacetylase function would be of great benefit in understanding how gene transcription is controlled, how the cell cycle is regulated, and how cells are signaled to undergo terminal differentiation and/or apoptosis. Elucidation of such mechanisms can lead to improved therapeutics for many diseases, in particular those characterized by cell proliferation or a lack of cell differentiation or apoptosis, for example, cancer.